PROJECT SUMMARY Gliomas are the most frequently occurring malignant brain tumor. Glioma cells diffusely invade the brain, and frequently can lead to seizures. However, evidence supporting seizure prophylaxis in individuals with brain tumors is inconclusive. Extensive research has focused on how glioma causes seizures, but it is not known whether seizures might cause or stimulate progression of glioma. If seizures were found to stimulate glioma progression, the imperative for treatment would be clear. Evidence suggests seizures may influence glioma formation or progression. First, cortical dysplasias, epileptogenic developmental lesions, often co-occur with forms of glioma. Second, recurrent seizures in early glioma are associated with poorer tumor outcomes. Third, in animal epilepsy models and human epilepsy, marked reactive gliosis frequently occurs . Finally, neuronal activity, including motor seizures, promotes oligodendrogenesis by eliciting a proliferative response of oligodendrocyte precursor cells (OPCs). As OPCs give rise to gliomas, this dysregulated neuronal activity may stimulate tumor growth. We have mouse models with genetic changes induced by retroviral vectors that cause predictable formation of gliomas from OPCs. We will use these models to examine the role of seizures in glioma formation and progression. We hypothesize that seizures could act via stimulation of glial cell precursors to promote or accelerate glial tumor formation. We propose to test this hypothesis by examining the effect of acute induced seizures on glial tumor progression in our mouse models. In Aim 1 we will examine the effects of acute provoked seizures on tumor progression in two mouse models, one with floxed Pten and p53 (two known tumor suppressors), one with floxed Pten only. In each of these models PDGF-IRES-Cre (PIC) retrovirus is injected into the rostral subcortical white matter of transgenic mice that carry floxed tumor suppressors, delivering the PDGF oncogene to produce reliable glioma formation. We will examine effects of seizures on glioma growth, tumor grade, and survival, while examining the roles of p53 and Pten in the link between seizures, abnormal glial proliferation and gliomagensis. In Aim 2 we will examine the effect of induced seizures on glioma development in a subsufficient model in which Pten and p53 are deleted in OPCs in subcortical white matter infected with retrovirus that expresses Cre, but does not express PDGF. We have shown that these mice do not form tumors. We will induce seizures using electrical stimulation via transcorneal electrodes in vivo, thus targeting stimulation to frontal circuits in which the tumor develops at the site of injection. Seizure induction will be timed before the occurrence of spontaneous seizures. Results could illuminate the relationship between tumor biology and epilepsy, and have important clinical implications. Demonstration that seizures may accelerate tumor progression would provide strong evidence, which does not currently exist, to support universal seizure prophylaxis in individuals with glial tumors.